Evaluation of Amides, Carbamates, Sulfonamides, and Ureas of 4-Prop-2-ynylidenecycloalkylamine as Potent, Selective, and Bioavailable Negative Allosteric Modulators of Metabotropic Glutamate Receptor 5.

Negative allosteric modulators (NAMs) of the metabotropic glutamate receptor 5 (mGlu) hold great promise for the treatment of a variety of central nervous system disorders. We have recently reported that prop-2-ynylidenecycloalkylamine derivatives are potent and selective NAMs of the mGlu receptor. In this work, we explored the amide, carbamate, sulfonamide, and urea derivatives of prop-2-ynylidenecycloalkylamine compounds with the aim of improving solubility and metabolic stability.

Reduced biliary sterol output with no change in total faecal excretion in mice expressing a human apolipoprotein A-I variant.

Background/aims: Apolipoprotein (apo)A-I(M) (ilano), is a molecular variant of apoA-I(wild-type), associated with dramatically low HDL-cholesterol levels, but no increased risk for cardiovascular disease. In view of the present uncertainties on the role of apoA-I in liver cholesterol removal by way of bile acids and neutral sterols, and of the greater capacity of apoA-I(M) (ilano) to remove arterial cholesterol, biliary sterol metabolism was evaluated in transgenic mice expressing apoA-I(M) (ilano).

Methods: ApoA-I(M) (ilano) mice were fed a high-cholesterol/high-fat diet, and compared with human apoA-I(wild-type) mice.

Rosuvastatin does not affect human apolipoprotein A-I expression in genetically modified mice: a clue to the disputed effect of statins on HDL.

Background And Purpose: Besides a significant reduction of low-density lipoprotein (LDL) cholesterol, statins moderately increase high-density lipoprotein (HDL) levels. In vitro studies have indicated that this effect may be the result of an increased expression of apolipoprotein (apo)A-I, the main protein component of HDL. The aim of the present study was to investigate in vivo the effect of rosuvastatin on apoA-I expression and secretion in a transgenic mouse model for human apoA-I.

Lupin (Lupinus albus) protein isolate (L-ISO) has adequate nutritional value and reduces large intestinal weight in rats after restricted and ad libitum feeding.

Background: A protein isolate from white lupin (Lupinus albus; L-ISO) has potential as a novel human food ingredient, but its nutritional effects are unknown.

Methods: We evaluated protein quality and effects on body composition in rats of isoenergic diets of L-ISO, lactalbumin, or casein with both restricted (10-day) and ad libitum (28-day)intake. The diets were equivalent in protein per se, but supplementation was used to balance essential amino acid levels.

Apolipoprotein A-I and the molecular variant apoA-I(Milano): evaluation of the antiatherogenic effects in knock-in mouse model.

No evidence of premature vascular disease is found in apolipoprotein A-I(Milano) (apoA-I(M)) human carriers, despite very low high density lipoprotein (HDL) cholesterol levels. Whether apoA-I(M) may impart a "gain of function" in atherosclerosis protection compared to wild-type apoA-I is hotly debated. To address this question, knock-in mice expressing human apoA-I or apoA-I(M) were crossed with atherosclerosis-susceptible mice expressing the human apoB/A-II transgene (h-B/A-II/A-I(Hu/Hu) and h-B/A-II/A-I(M)(Hu/Hu)).

Targeted replacement of mouse apolipoprotein A-I with human ApoA-I or the mutant ApoA-IMilano. Evidence of APOA-IM impaired hepatic secretion.

Despite a pro-atherogenic profile, individuals carrying the molecular variant (R173C) of apolipoprotein (apo)A-I, named apoA-I(Milano) (apoA-I(M)), appear to be at reduced risk for cardiovascular disease. To develop an in vivo system to explore, in a controlled manner, the effects of apoA-I(M) on lipid metabolism, we have used the gene targeting technology, or "gene knock-in" (gene k-in), to replace the murine apoA-I gene with either human apoA-I or apoA-I(M) genes in embryonic stem cells. As in human carriers, mice expressing apoA-I(M) (A-I(M) k-in) are characterized by low concentrations of the human apolipoprotein and reduced high density lipoprotein cholesterol levels, compared with A-I k-in animals.